ABSTRACT Adropin is a recently identified and highly conserved polypeptide abundantly expressed in the brain. Adropin plays a critical role in the regulation of endothelial function, insulin sensitivity, and metabolism. Recent findings from our group and others reveal that adropin can significantly reduce endothelial permeability in rat brain and human vascular endothelial cells. Clinical studies show a significant association between low plasma levels of adropin and endothelial dysfunction in several human diseases. Endothelial dysfunction is one of the critical factors contributing to the pathogenesis of ischemic stroke. Deficient production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) is a key factor contributing to endothelial dysfunction in diabetes, obesity, and hyperlipidemia, which are important risks factors for stroke. Our overall goal in this proposal is to demonstrate the protective role of adropin in ischemic stroke and investigate the underlying molecular mechanisms of this protection. Our hypothesis is that adropin confers protection against ischemic stroke injury by reducing damage to the blood-brain barrier (BBB)/neurovascular unit. Our preliminary data support this hypothesis by showing that treatment with synthetic adropin dramatically reduces stroke injury in a mouse model, which was associated with a significant increase in eNOS phosphorylation and reduced BBB damage. Moreover, adropin protection was completely abolished in eNOS deficient mice suggesting an eNOS-dependent mechanism underlying the protective effects of adropin in stroke. Aim 1 is to determine the long-term effects of adropin treatment on infarct size and functional recovery in a mouse model of ischemic stroke. In Aim 2, we will determine the ability of adropin to reduce the detrimental effects of endothelial dysfunction, oxidative stress, and neuroinflammation on BBB function following ischemic stroke. In Aim 3, we will test the neuroprotective efficacy of adropin in relation to age, sex, species, and comorbid conditions (obesity and diabetes). It is our expectation that this study will provide significant knowledge on the protective efficacy of adropin in ischemic stroke. Such results would be expected to have an important positive impact, since they would set the stage for expanded preclinical work on the neuroprotective efficacy of adropin in cerebral ischemia, and would identify novel and much-needed approaches to reduce the devastating consequences of neurovascular injury after stroke.